ERG gene rearrangements are common in prostatic small cell carcinomas

Small cell carcinoma of the prostate is an unusual and aggressive subtype, accounting for 0.5–2% of all prostate cancers.1,2 Typically, the diagnosis is made using morphological criteria as most small cell carcinomas of prostatic origin share the classic ‘oat-cell’ morphology with those described in the lung. Approximately 50% of the time, prostatic small cell carcinoma occurs concurrently with usual-type acinar carcinoma and the two components may be intermingled, thus suggesting a common origin; however, molecular evidence for clonal evolution has been limited.1–3 When prostatic small cell carcinomas occur without an associated acinar component, particularly in a metastatic site, it can be difficult to determine the site of origin of the tumor. Several recent studies have shown that immunohistochemical markers of prostatic origin, including PSA, PSAP, PSMA and p501s, can be negative in up to 80% of small cell carcinoma cases.4–6 Further complicating the situation, TTF-1, a common marker of lung carcinoma is positive in >50% of cases.5,6 Recently, a bioinformatics approach uncovered a gene rearrangement present in 40–60% of conventional prostatic acinar carcinoma cases, making it the most common rearrangement identified in human cancer to date.7 This rearrangement occurs between an androgen-regulated gene, TMPRSS2 (21q22.3) and an ETS transcription factor family member, most commonly ERG (21q22.2), resulting in a gene fusion product.7–9 This gene fusion can occur through a small deletion on chromosome 21 (seen in approximately two-thirds of acinar cases displaying ERG rearrangement) or through a translocation.9,10 Although the clinicopathological significance of this genetic rearrangement has remained controversial, it is clear that ERG rearrangements are specific and sensitive for prostatic acinar carcinomas.11–15 Despite the numerous studies of TMPRSS2–ERG gene fusions in prostatic adenocarcinomas, only one recent small study has documented the occurrence of this rearrangement in androgen-independent metastases of prostatic small cell carcinomas.16 However, data on the rates of ERG rearrangement in primary prostatic small cell carcinomas and the concordance of ERG rearrangements in concurrent small cell and acinar carcinoma tumors are lacking. In this study, we studied the rate of ERG gene rearrangement in 29 cases of primary prostatic small cell carcinomas by fluorescence in situ hybridization (FISH). Given recent reports that establish an etiological relationship between the androgen-signaling axis and ERG rearrangement, we also examined the expression of ERG protein, androgen receptor (AR) and NKX3-1 (an androgen-regulated transcription factor), in these cases.17–19